Salt-sensitive hypertension accounts for 40% of the hypertensives worldwide. Still, molecular mechanisms of salt-sensitivity are not well understood. One theory attributes endogenous CTS a central role in the pathogenesis of salt-sensitive hypertension. Two CTS, endogenous ouabain and MBG, coexist in mammalian tissues. MBG acts as a selective inhibitor of ouabain-resistant alpha-1 isoform of NKA, the main isoform in the kidney, vascular smooth muscle and adult cardiomyocytes. In Dahl salt-sensitive rats (DS) on a high NaCl intake, brain endogenous ouabain triggers peripheral MBG, which raises the BP. In humans, moderate NaCl-loading causes increase in MBG production. In order to define the relationships between CTS, high NaCl intake, BP and natriuretic function, we analyzed levels of endogenous ouabain and MBG in two human studies, SALT (NIA), and SARAH (Lund University, Malmo, Sweden) in collaboration with Drs. David E. Anderson and Olle Melander. The results of SALT study demonstrate that in post-menopausal women, MBG is implicated in renal sodium excretion, and suggest that a relative failure to increase natriuretic MBG levels in response to NaCl-loading with increasing age could be a factor in the increase in NaCl sensitivity of BP with aging. Because subjects in the present study were normotensive, our findings do not necessarily reflect salt sensitivity or NaCl-induced MBG production in hypertensive patients. In the SARAH study, 39 subjects (20 males and 19 females;5311 years) were examined under baseline conditions (NaCl-intake not standardized) and thereafter received 50 mmol NaCl/day for 8 weeks in provided meals and drinks. In addition, NaCl capsules (100 mmol/day) and corresponding placebo capsules were administered for 4 weeks each in random order. MBG and 24-hour ambulatory BP were measured at baseline, after 4 weeks of 50 mmol/day (low salt, LS) and after 4 weeks of 150 mmol/day (high salt, HS). The shift in dietary salt from LS to HS caused elevations of SBP and DBP in both genders and was associated with an increase in plasma MBG. Similar to that in SALT study, plasma MBG at HS positively correlated with renal sodium excretion in both genders. In contrast to SALT, in SARAH, in both genders renal MBG excretion did not exhibit negative correlation with SBP. Levels of SBP, however, negatively correlated with renal sodium excretion in females, as observed in SALT study, but not in male subjects. Changes in SBP in females, but not in males exhibited a borderline significant positive correlation with age (like in SALT study). In females >45 years old this correlation became strong and significant (R= -0.66, P=0.01). In both sexes renal MBG excretion on HS negatively correlated with age, as in SALT study, but a fold of increase of MBG excretion from LS to HS (ratio of MBG on HS to MBG on LS) in males, but not in females, exhibited a strong positive correlation with age. In males, but not in females, baseline plasma MBG was directly related to 24h DBP on HS. Data from both studies suggest that MBG is an important determinant of salt-sensitivity of BP and that its reaction to salt and its relation to salt sensitivity of BP differs by age and gender. While in older females, a relative failure in MBG production may cause volume expansion and contribute to hypertension, in males, aging is associated with lower baseline MBG levels, but a greater responsiveness of MBG to HS. Note that a similar relationship was found in aging male Sprague-Dawley rats.